Tolcapone

Results of well designed studies indicate that oral tolcapone is an effective adjunct to levodopa plus a peripheral dopa-decarboxylase inhibitor (DDCI) in patients with fluctuating Parkinson’s disease. Tolcapone significantly improves levodopa-induced motor fluctuations and significantly reduces levodopa requirements. The drug is generally well tolerated, with the most commonly occurring adverse events being dopaminergic related. Thus, tolcapone is a useful option in patients with fluctuating Parkinson’s disease who are receiving levodopa/DDCI and are not responding to, or are not candidates for, other adjunctive treatments.

Tolcapone inhibited erythrocyte COMT activity in healthy volunteers; inhibition was rapid and reversible. COMT inhibition of ≈80% occurred at a tolcapone dose of 200mg. The efficacy of tolcapone as an adjunct to levodopa in patients with Parkinson’s disease has primarily been attributed to its ability to inhibit peripheral COMT. However, results of a study in patients with Parkinson’s disease, as well as results of animal studies, suggest that tolcapone also has central inhibitory activity. Tolcapone potentiates the beneficial motor effects of levodopa in patients with Parkinson’s disease receiving single 50–800mg doses of the drug in addition to levodopa/DDCI.

In in vitro studies, tolcapone uncoupled oxidative phosphorylation in isolated rat liver mitochondria. This uncoupling action has been linked to toxicity in cultured human neuroblastoma cells, as well as to hepatotoxicity in an in vivo study in rats.

Tolcapone is rapidly absorbed and has an absolute bioavailability of ≈65%. It is highly plasma protein bound (>99.9%) and extensively metabolised, with an elimination half-life (ty1/2) of ≈2–3 hours. Tolcapone has clinically relevant effects on levodopa pharmacokinetics, resulting in more constant plasma concentrations of levodopa. Compared with levodopa/DDCI alone, tolcapone increased the area under the plasma concentration-time curve of levodopa and prolonged its ty1/2 in both healthy volunteers and patients with Parkinson’s disease, without altering the maximum plasma concentration (Cmax) or time to Cmax.

The efficacy of tolcapone 100 or 200mg three times daily as add-on therapy to levodopa/DDCI has been examined in patients with fluctuating Parkinson’s disease (n =40–215) in randomised studies of 3 weeks to 3 months’ duration. The addition of tolcapone versus placebo to levodopa/DDCI improved levodopa-induced motor fluctuations, with significant increases in ‘on’ time and reductions in ‘off’ time (primary endpoint). Tolcapone also reduced the total daily levodopa dosage to a significantly greater extent than placebo in all but one study. A ‘switch’ study was performed in which fluctuating Parkinson’s disease patients optimised on entacapone therapy were either left on entacapone or crossed over to receive tolcapone for 3 weeks. A significantly greater proportion of tolcapone than entacapone recipients had an increase in ‘on’ time of ≥3 hours per day. In addition, tolcapone reduced total daily levodopa requirements to a significantly greater extent than the dopamine agonist bromocriptine.

The efficacy of tolcapone 100 or 200mg three times daily has also been examined in patients with stable Parkinson’s disease (n = 97–298) in two short-term studies and one longer-term study. Tolcapone was associated with significant improvements from baseline in various endpoints in one short-term study, although there were no significant differences between tolcapone and placebo in the other short-term study. In the longer-term study, the reduction from baseline in the Unified Parkinson’s Disease Rating Scale subscale II score seen with tolcapone was significantly greater than the increase seen with placebo at 6 months (primary endpoint); improvements were maintained after 12 months’ therapy.

Tolcapone 100 or 200mg three times daily was generally well tolerated in patients with fluctuating or stable Parkinson’s disease in placebo-controlled studies of up to 12 months’ duration. Dopaminergic-related events were the most frequently reported adverse events in tolcapone recipients, and included dyskinesia, nausea, orthostatic complaints, sleep disorders/insomnia, muscle cramps, somnolence, excessive dreaming, anorexia, vomiting, dystonia, confusion and hallucination. Nondopaminergic adverse events included diarrhoea, dizziness, headache, constipation, falling, upper respiratory tract infection, increased sweating, dry mouth and urine discoloration.

A review of clinical trial data reported increases in aminotransferase levels of >3-fold above the upper limit of normal in 1.3% and 3.7% of patients receiving tolcapone 100 or 200mg three times daily; elevations in ALT and AST levels occurred within 6 weeks to 6 months of commencing tolcapone therapy. About half of patients who continued tolcapone therapy experienced normalisation of aminotransferase levels within 1–3 months; in patients who discontinued tolcapone, normalisation occurred in 2–3 weeks. Tolcapone has been associated with cases of severe hepatocellular injury during postmarketing surveillance, with three cases of fatal fulminant hepatic failure reported up to October 1998; the liver function of these patients had not been monitored appropriately. However, following the subsequent introduction of stringent liver function monitoring guidelines in the US, there have been no cases of death due to liver failure attributable to tolcapone.